The role of modelling and simulation in the paediatric investigation plan of a xanthine oxidase inhibitor for tumor lysis syndrome prevention
G. Smania (1), P. Mazzei (1), C. Piana (1), S. Baldini (1), C Simonelli (1), A. Capriati (1), A. Pellacani (1)
(1) Menarini Ricerche, Florence (Italy).
Objectives: Febuxostat (FBX) is an oral xanthine oxidase inhibitor which demonstrated its superiority versus allopurinol in controlling serum uric acid levels in adult patients at risk of tumor lysis syndrome (TLS) [1]. Following the recommendations outlined in the EMA reflection paper [2], this work presents the concept and plan for the extrapolation of FBX efficacy and safety data from adults to paediatric patients aged 6-17 years old (target population), emphasising the role of modelling and simulation (M&S) in the paediatric investigation plan (PIP) agreed with the Agency.
Methods: Since FBX elimination pathways are fully mature at 6 years of age [3-6], it is expected that the PK between the target and adult population can be scaled based only upon weight. In addition, considering TLS similarities between the two populations, it is reasonable to assume a comparable response to FBX as well as a similar PK-PD relationship. On this ground, FBX efficacy and safety can be extrapolated from adults and a full clinical development plan could be skipped in favour of a single phase I/II PK-PD study. Dose selection in this study was based on a 2-compartment pop-PK model in adults, which allowed to identify paediatric doses targeting the efficacious and safe exposure range observed in adults. Weight-based allometry was used to scale clearances and volumes [7]. Two age groups were considered: children (6-11 years) and adolescents (12-17 years); the candidate doses were 40 mg, 60 mg, 80 mg and 120 mg QD.
Results: PK simulations revealed that children dosed up to 60 mg would achieve the target AUC and Cmax while remaining below the highest safe exposure observed in adults. With respect to adolescents, doses of 40 mg and 60 mg are not sufficiently high to guarantee the attainment of efficacious exposures. On the contrary, exposures at 80 mg and 120 mg are expected to be within the efficacious and safe exposure range. Should these predictions not be confirmed by actual data, dose recommendations in the target population will be based on PK simulations of alternative dosages and on the data collected in the paediatric study, without the need to run further clinical trials.
Conclusions: M&S played a pivotal role in the definition of the FBX PIP by supporting the selection of safe, efficacious and informative doses to be tested in the paediatric trial and, together with the extrapolation approach, allowed to minimize the number of paediatric patients exposed to clinical investigations.
References:
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